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Role of replication machinery disassembly in cancer development and treatment


Project Description

Our recent work provided the first insights into the mechanism of replication machinery (replisome) unloading at the termination of DNA replication, making use of Xenopus laevis egg extract, which provides a simple cell-free system that recapitulates DNA replication. We found that the replicative helicase is polyubiquitylated at termination by CUL2LRR1 ubiquitin ligase (LRR1 is a substrate-specific receptor of the ligase), which promotes removal of the helicase from chromatin. Moreover, we described a back-up pathway of replisome disassembly in mitosis regulated by TRAIP ubiquitin ligase. These findings led to the first model of eukaryotic replisome disassembly.

TRAIP knockout mice are embryonic lethal and our unpublished data indicate that Lrr1-/- mice are also embryonic lethal, indicating the importance of this pathway for cell survival. TRAIP is important for resolution of replication stress and its mutations lead to primordial dwarfism. We have also shown that in human cells, blocking the unloading of the replisome leads to activation of the DNA damage response. Crucially, we do not know the consequences of dysregulation of the replisome disassembly process for human health.

Replication factors are often upregulated in cancer and are required for its growth: high levels of LRR1 and TRAIP expression correlate with poor prognosis in some cancers. Moreover, replication factors, when mutated, can contribute to cancer chromosomal instability (CIN) and drive cancer development. Importantly, public datasets report a number of mutations within LRR1 and TRAIP that are observed in cancer.

Factors that drive the assembly of the helicase are currently being explored as anti-cancer therapy targets in tumours with defects in replication. Inhibition of replisome disassembly is likely also provide a valid strategy for therapy. Finally, the existence of two replisome disassembly pathways (in S-phase and in mitosis) provides a perfect synthetic lethality scenario, where cancerous cells defective in one of the pathways could be killed by inhibition of the other.

Aim 1. Is defective replisome disassembly a promoter of genome instability and cancer?

Aim 2. Can we target the replisome disassembly pathway for cancer treatment?

Aim 3. Can we exploit the synthetic lethality of two replisome disassembly pathways?

Outcome
We will establish direct links between replisome disassembly and cancer development and assess potential cancer treatment targets.

Candidate specification
We are looking for an enthusiastic PhD candidate from UK or EU with a first or upper-second UK Bachelor’s degree or a recognised taught Masters degree in a relevant subject – Biology, biochemistry, molecular biology etc. Overseas qualifications of an equivalent standard from a recognised higher education institution are also accepted.
Previous research experience, ambitious, creative and a good team worker.
During the interview students will be asked to prepare 15 min presentation of a previous research project they have undertaken. Student’s ability to present and discuss their work, general knowledge of the research subject and critical thinking will be assessed.

Funding Notes

This project is part of the Global Challenges Scholarship.
The award comprises:

Full payment of tuition fees at UK Research Councils UK/EU fee level (£4,327 in 2019/20), to be paid by the University;
An annual tax-free doctoral stipend at UK Research Councils UK/EU rates (£15,009 for 2019/20), to be paid in monthly instalments to the Global Challenges scholar by the University;
The tenure of the award can be for up to 3.5 years (42 months).

References

Moreno et al. Science 2014,
Sonneville et al. NCB 2017
Priego Moreno et al. BioRxiv 2018

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